The Sclerostin-Independent Bone Anabolic Activity of Intermittent PTH Treatment Is Mediated by T-Cell Produced Wnt10b

• Type of Material: Article
• Authors: Jau-Yi Li, Emory University; Lindsey D. Walker, Emory University; Abdul Malik Tyagi, Emory University; Jonathan Adams, Emory University; M. Neale Weitzmann, Emory University; Roberto Pacifici, Emory University
• Language: English
• Date: 2014-01-01
• Publisher: Wiley
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2014 American Society for Bone and Mineral Research
• Final Published Version (URL): http://dx.doi.org/10.1002/jbmr.2044
• Title of Journal or Parent Work: Journal of Bone and Mineral Research
• ISSN: 0884-0431
• Volume: 29
• Issue: 1
• Start Page: 43
• End Page: 54
• Grant/Funding Information: MNW gratefully acknowledges financial support by the Biomedical Laboratory Research & Development Service of the VA Office of Research and Development (5I01BX000105), NIAMS (AR059364, AR056090, and AR053607), NIA (AG040013), and by the Georgia Research Alliance.; This study was supported by grants from the National Institutes of Health (AR54625, AR49659, and AR061453).
• Keywords: SCL; T-cells; bone; antibody; PTH; WNT10B
• Research Categories: Health Sciences, Pathology

Abstract

Both blunted osteocytic production of the Wnt inhibitor sclerostin (Scl) and increased T‐cell production of the Wnt ligand Wnt10b contribute to the bone anabolic activity of intermittent parathyroid hormone (iPTH) treatment. However, the relative contribution of these mechanisms is unknown. In this study, we modeled the repressive effects of iPTH on Scl production in mice by treatment with a neutralizing anti‐Scl antibody (Scl‐Ab) to determine the contribution of T‐cell–produced Wnt10b to the Scl‐independent modalities of action of iPTH. We report that combined treatment with Scl‐Ab and iPTH was more potent than either iPTH or Scl‐Ab alone in increasing stromal cell production of OPG, osteoblastogenesis, osteoblast life span, bone turnover, bone mineral density, and trabecular bone volume and structure in mice with T cells capable of producing Wnt10b. In T‐cell–null mice and mice lacking T‐cell production of Wnt10b, combined treatment increased bone turnover significantly more than iPTH or Scl‐Ab alone. However, in these mice, combined treatment with Scl‐Ab and iPTH was equally effective as Scl‐Ab alone in increasing the osteoblastic pool, bone volume, density, and structure. These findings demonstrate that the Scl‐independent activity of iPTH on osteoblasts and bone mass is mediated by T‐cell–produced Wnt10b. The data provide a proof of concept of a more potent therapeutic effect of combined treatment with iPTH and Scl‐Ab than either alone. © 2014 American Society for Bone and Mineral Research.